Cultures of skin fibroblasts, peripheral blood lymphocytes and lymphoblastoid cell lines from normal and cancer-prone individuals, as well as neoplastic cells transformed in culture or in vivo, are utilized in evaluating the relationship between radiation-induced chromosomal DNA damage, deficient DNA repair, genetic instability, cancer susceptibility and neoplastic transformation. An increased incidence of chromatid damage after x-irradiation, specifically during G-2 phase of the cell cycle, is associated with both a predisposition to cancer and neoplastic transformation and can provide the basis of a test for genetic susceptibility to cancer. Efforts are currently directed toward developing such a cytogenetic assay using skin fibroblasts, peripheral blood lymphocytes or lymphoblastoid cell lines. A genetic basis for this radiosensitivity with localization of genes to specific chromosomes is indicated from studies with somatic cell hybrids, inbred strains of mice and congenic mouse strains; studies are in progress to localize and map such gene loci. The chromosomal radiosensitivity appears to result from deficient DNA repair during G-2. Another aspect of this project is to develop a reproducible transformation system with human epidermal keratinocytes as an in vitro model for following the progression of biologic, cytomorphologic and biochemical charges leading to neoplastic transformation, with particular emphasis on the acquisition of DNA repair deficiencies and genetic instability.